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US6251295B1 - Method for recirculation washing of blood cells - Google Patents

Method for recirculation washing of blood cells Download PDF

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Publication number
US6251295B1
US6251295B1 US09/004,344 US434498A US6251295B1 US 6251295 B1 US6251295 B1 US 6251295B1 US 434498 A US434498 A US 434498A US 6251295 B1 US6251295 B1 US 6251295B1
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Prior art keywords
suspension
bag
port
blood cells
cells
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US09/004,344
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English (en)
Inventor
Craig L. Johnson
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Nexell Therapeutics Inc
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Nexell Therapeutics Inc
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Priority to US09/004,344 priority Critical patent/US6251295B1/en
Assigned to NEXELL THERAPEUTICS INC. reassignment NEXELL THERAPEUTICS INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: JOHNSON, CRAIG L.
Priority to AT99901408T priority patent/ATE314869T1/de
Priority to CA002317756A priority patent/CA2317756C/fr
Priority to PCT/US1999/000535 priority patent/WO1999034848A1/fr
Priority to JP2000527295A priority patent/JP4307714B2/ja
Priority to EP99901408A priority patent/EP1058564B1/fr
Priority to CA002644322A priority patent/CA2644322A1/fr
Priority to CA002569912A priority patent/CA2569912C/fr
Priority to AU21110/99A priority patent/AU744878B2/en
Priority to ES99901408T priority patent/ES2257028T3/es
Priority to DE69929303T priority patent/DE69929303T2/de
Priority to US09/863,485 priority patent/US20010035377A1/en
Publication of US6251295B1 publication Critical patent/US6251295B1/en
Application granted granted Critical
Priority to JP2007297162A priority patent/JP4829205B2/ja
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3621—Extra-corporeal blood circuits
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
    • A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
    • A61M1/26—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes and internal elements which are moving
    • A61M1/262—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes and internal elements which are moving rotating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3601—Extra-corporeal circuits in which the blood fluid passes more than once through the treatment unit
    • A61M1/3603—Extra-corporeal circuits in which the blood fluid passes more than once through the treatment unit in the same direction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3618—Magnetic separation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3692—Washing or rinsing blood or blood constituents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/02—Blood transfusion apparatus
    • A61M1/0209—Multiple bag systems for separating or storing blood components
    • A61M1/0218—Multiple bag systems for separating or storing blood components with filters

Definitions

  • This invention relates to recirculation washing of blood cells using a spinning membrane filter, and in particular to recirculation washing of blood cells in a magnetic cell selection apparatus.
  • FIGS. 7 and 8 in the Fischel patent illustrate a cell washing modification in which a porous wall is interposed between the membrane and the inner wall of the housing.
  • FIG. 6 in the Schoendorfer patent illustrates introduction of a rinse solution with the blood.
  • Duff U.S. Pat. No. 5,234,608, issued Aug. 10, 1993 discloses a spinning membrane filter of the type which is preferred for use in conjunction with this invention. According to the disclosure, cell-rich concentrate is removed from the upper portion of the gap between the membrane and the inner wall of the housing, cell-poor plasma filtrate is removed from the bottom center of the spinning membrane filter. Source cell suspension is mixed with cell-rich concentrate and introduced to the lower portion of the gap area.
  • U.S. Pat. No. 5,536,475 discloses a semi-automated instrument for selection of blood cells using paramagnetic beads which are coated with a binding agent such as an antibody which binds specifically to the cells to be selected.
  • the instrument comprises a primary magnet associated with a primary container and a secondary magnet associated with a secondary container. Blood cells, liquid and beads are agitated in the primary container to form a conjugate between the beads and the selected cells. The primary magnet is then moved into a position adjacent the primary container to magnetically capture the bead/cell conjugate and the non-selected cells and liquid are removed. The primary magnet is then moved into a position away from the primary container to release the bead/cell conjugate.
  • Wash solution is added and the contents of the primary container are agitated, then the primary magnet is moved into the position adjacent the primary container to again capture the bead/cell conjugate and the wash solution is removed.
  • the primary magnet is again moved into a position away from the primary container to release the bead/cell conjugate.
  • Liquid containing a reagent which releases the selected cells from the beads is added and the contents are again agitated.
  • the primary magnet is again moved into the position adjacent the primary container to capture the beads.
  • the released cells and liquid are introduced to the secondary container.
  • the secondary container is positioned adjacent to the secondary magnet to capture any beads which may have escaped the primary magnet.
  • the instrument is used with a disposable set comprising plastic bags for wash liquid, cell suspension and bead suspension, interconnected with plastic tubing.
  • the semi-automated instrument disclosed in the Moubayed et al. patent is sold by Baxter Healthcare Corporation, under the trademark Isolext® 300 SA.
  • a modified version of the instrument is sold by the Baxter Healthcare Corporation under the trademark Isolex® 300i.
  • the 300i differs from the 300 SA in that it is fully automated and it includes a spinning membrane filter for washing the selected cells and also for removing platelets from the source cells prior to selection.
  • Deniega discloses a tubing set which includes a spinning membrane filter and a reservoir for platelet-poor packed blood cells. The reservoir has a top and bottom port. Packed cells from the outlet of the spinning membrane filter enter through the top inlet port of the reservoir. Whole blood from a patient enters through the bottom inlet port.
  • Recirculation washing of selected blood cells is performed in the Isolex® 300i utilizing the spinning membrane filter in conjunction with a recirculation wash bag which has both inlet and outlet ports at the bottom and no port at the top.
  • the bag is a 600 ml bag with the inlet and outlet ports separated by about 2 inches.
  • the bag has been able to concentrate cell suspensions that normally start at about 400 ml. This bag performed better when it was occasionally massaged. This is the only way to process more than about 5 ⁇ 10 10 cells in the bag.
  • This invention includes a method, a bag and a disposable set for recirculation washing of blood cells.
  • the invention can be used for washing of blood cells in a magnetic cell selection instrument, but can also be used for washing whole blood or other blood cell products.
  • the recirculation wash bag is a flexible plastic bag which has a top port and a bottom port.
  • an integral coarse filter comprising a tube of semi-rigid plastic mesh extends from the top port into the bag. This filter provides mild resistance to larger cell aggregates.
  • the bag includes a bubble trap at the top comprising tubing extending into the bag from the top port.
  • the bag includes both the semi-rigid integral filter and the bubble trap; the tubing for the bubble trap fits inside the plastic mesh tube to provide a space to accumulate air around the tubing.
  • the method of the invention utilizes a flexible plastic recirculation wash bag and a spinning membrane filter.
  • the spinning membrane filter has an inlet port for a diluted suspension of blood cells in buffer solution, a first outlet port for filtrate, and a second outlet port for a concentrated suspension of blood cells in buffer solution.
  • the recirculation wash bag has a top outlet port and a bottom inlet port.
  • the recirculation wash bag includes the integral coarse filter and bubble trap described above.
  • the method comprises withdrawing a suspension of blood cells in buffer solution from the recirculation wash bag through the top port, mixing the suspension with additional buffer solution to form a diluted suspension of blood cells in buffer solution, feeding the diluted suspension into the spinning membrane filter through the inlet port, withdrawing filtrate comprising buffer solution from the spinning membrane filter through the first outlet port, withdrawing a concentrated suspension of blood cells in buffer solution from the spinning membrane filter through the second outlet port, feeding the concentrated suspension into the bag through the bottom port, and continuing the recirculation washing until the desired amount of washing has been achieved.
  • a method for determining when the desired amount of washing has been achieved, based on an estimate of “residual,” is described below.
  • the residual represents the target component for reduction (e.g., platelets, antibody, etc., as described below).
  • the suspension of blood cells withdrawn through the top port of the recirculation wash bag is mixed with unwashed blood cells as well as buffer solution before feeding the diluted suspension into the spinning membrane filter.
  • the unwashed blood cells include platelets
  • the filtrate comprises a suspension of platelets in buffer solution
  • the recirculation washing is continued until the platelet content of the concentrated suspension of cells has been reduced to the desired level.
  • the recirculation wash bag at the beginning of the recirculation wash procedure contains, in addition to blood cells, an antibody which specifically binds an antigen on certain of the blood cells, the filtrate comprises a suspension of the antibody in the buffer solution, and the recirculation washing continues until the concentrated suspension of cells contains the desired amount of excess, unbound antibody.
  • the recirculation wash bag at the beginning of the recirculation wash procedure contains blood cells which have been selected in a magnetic cell selection procedure and a peptide release agent which was used to release the selected cells from a cell/magnetic bead conjugate
  • the filtrate comprises a solution of the peptide release agent in buffer solution
  • the recirculation washing is continued until the peptide release content of the concentrated suspension of cells has been reduced to the desired level.
  • the disposable set of the invention comprises the recirculation wash bag and the spinning membrane filter having ports as described above, and a filtrate bag, plus associated tubing, including tubing for a buffer solution bag.
  • Plastic tubing connects the top port of the recirculation wash bag to a mixing zone.
  • Plastic tubing with a buffer bag spike coupler at one end is connected to the same mixing zone.
  • the mixing zone is connected by plastic tubing to the inlet port of the spinning membrane filter.
  • the first outlet port of the spinning membrane filter is connected by plastic tubing to the inlet port of the filtrate bag.
  • the second outlet port of the spinning membrane filter is connected by plastic tubing to the bottom port of the recirculation wash bag.
  • the disposable set may also include other bags and associated tubing for use in a magnetic cell selection instrument, such as a bag for antibody suspension in buffer solution, a bag for peptide release agent solution in buffer solution, a bag for a suspension of the nonselected cells in buffer solution, and an end product bag for washed cells.
  • a bag for unwashed cells also referred to as a cell source bag
  • a bag for buffer solution may be included in the set, but in the preferred embodiment these items are supplied separately.
  • a flexible recirculation wash bag with ports at the top and bottom and flow from bottom to top provides several advantages as compared to a bag with inlet and outlet ports at the bottom, as currently used on the Isolex® 300i.
  • using a flexible bag allows the volume to be varied depending on the number of cells. Exiting from the top has the advantage of removing the less dense supernatant preferentially. This aids in making the concentration ratio high. (The importance of high concentration ratio is discussed below). For large volumes or slow flow rates, some sedimentation of the larger cells also aids in reducing the cell concentration at the outlet port.
  • the system has the advantage of having the most washed and most concentrated cells at the bottom with the least washed and least concentrated cells at the top. Additional advantages include the following: (1) allows accurate residual estimates which in turn allow optimal residual levels instead of just reduction; (2) provides more uniform processing of cells which leads to a more uniform product for the selection process; (3) manual massaging of the bag during the wash is not required, permitting hands-free operation.
  • FIG. 1 illustrates the preferred embodiment of the recirculation wash bag of this invention.
  • the recirculation wash bag having the configuration shown in FIG. 1 is referred to as the IsoFlowTM bag.
  • FIG. 2 illustrates a disposable set of this invention which is adapted for use on a magnetic cell selection device such as the Isolex® 300i.
  • FIG. 3 illustrates a disposable cell wash set of the invention which is adapted for use on a stand-alone cell washing apparatus.
  • the IsoFlowTM bag is indicated generally by the numeral 5.
  • the bag is made of a flexible plastic such as and includes bottom port 1 and top port 2 .
  • An integral coarse filter comprising a tube of semi-rigid plastic mesh 3 extends from the top port into the bag to within about 1 ⁇ 2 to 3 inches, preferably about 1 inch, from the bottom of the bag.
  • the mesh tube is about 1 ⁇ 2 to about 1.5 inches in diameter, preferably about 1 inch in diameter, and is preferably closed at its lower end.
  • the tube's mesh (opening) size is in the range of about 80-400 microns, preferably about 230 microns.
  • the bag includes a bubble trap at the top which is created by inserting tubing 4 into the top port about 1 ⁇ 2 to 3 inches, preferably about 1.5 inches.
  • Suitable materials of construction include polyvinyl chloride (PVC) for the bag, polyester (e.g. Cleartuf®, shell) for the mesh tube filter, and PVC for the tubing.
  • Volume of the bag can vary, but will generally be between 100 and 1500 ml. As presently designed for use on the Isolex® 300i, the bag holds a volume of 400 ml.
  • the mesh could be replaced by some other semi-rigid, rigid or combination structure that facilitates flow from bottom to top.
  • the disposable set of this invention comprises the, IsoFlowTM bag 5 and spinning membrane filter 6 and associated tubing, including tubing for connecting a bag containing buffer solution.
  • Spinning membrane filter 6 (sometimes referred to simply as “spinning membrane” or “spinner”) has the construction shown in FIG. 2 of Duff U.S. Pat. No. 5,234,608.
  • the membrane is a nominal 4 micron polycarbonate membrane.
  • the buffer solution bag is not shown, but is indicated at 7 ; it is a standard flexible plastic bag with a bottom outlet port, and is supplied separately.
  • the top port 2 of IsoFlowTM bag 5 is connected by tubing 8 having a sampling device 8 a to the bottom right channel 9 b (indicated by dotted lines) of clamp manifold 9 .
  • Channel 9 b is a mixing zone for mixing cells from IsoFlowTM bag 5 with buffer solution from bag 7 and (in the platelet separation step described below) with unwashed cells from bag 44 .
  • Channel 9 b of clamp manifold 9 is connected by tubing 10 to the inlet port 11 of spinning membrane filter 6 .
  • the bottom port 1 of IsoFlowTM bag 5 is connected by tubing 12 to the bottom left channel of clamp manifold 9 and tubing 13 connects the bottom left channel of clamp manifold 9 to the outlet port 14 of spinning membrane filter 6 .
  • Tubing 15 connects the outlet port of buffer solution bag 7 to the top right channel of clamp manifold 16 ; tubing 17 connects the top right channel of clamp manifold 16 to the bottom left channel of clamp manifold 18 ; tubing 19 connects the bottom left channel of clamp manifold 18 to the bottom right channel of clamp manifold 18 and tubing 20 connects the bottom right channel of clamp manifold 18 to the bottom right channel 9 b of clamp manifold 9 .
  • Tubing 15 is connected to a buffer bag spike coupler 21 and a sterilizing filter 22 .
  • Tubing 23 connects filtrate outlet port 24 of spinning membrane filter 6 with the top right channel of clamp manifold 25 .
  • Tubing 26 connects the top right channel of clamp manifold 25 with Y-connector 27 .
  • Tubing 28 connects Y-connector 27 to the inlet port 29 of filtrate (waste) bag 30 .
  • a clamp 31 On tubing 28 is a clamp 31 .
  • Tubing 32 connects Y-connector 27 to Y-connector 33 .
  • Tubing 32 carries a clamp 40 .
  • Tubing 34 connects Y-connector 33 to inlet port 35 of waste bag 36 .
  • Tubing 37 connectes Y-connector 33 to inlet port 38 of waste bag 39 .
  • Tubing 41 connects the top right channel of clamp manifold 25 to pressure transducer protector 42 .
  • clamp manifolds There are three configurations of clamp manifolds shown in FIG. 2 . All configurations have clamps capable of obstructing the tubing that runs through them on a flat platen (not shown) in the center of the manifolds.
  • the dotted lines in the upper and/or lower portions of the clamp manifolds indicate the locations of channels within the manifolds.
  • the dotted lines in clamp manifold 45 show that the bottom channel connects all 4 tubes.
  • the dotted lines in clamp manifolds 9 and 18 show that there are two bottom channels—the left channel connects the two left tubes and the right bottom connects the two right tubes.
  • the dotted lines in clamp manifolds 16 and 25 show that the bottom left channel connects the tubes on the left and the top right channel connects the tubes on the right.
  • the disposable set of the invention also includes other bags and containers and associated tubing adapted for use on a magnetic cell separation instrument such as the the Isolex® 300i.
  • Tubing 43 connects a cell source bag (not shown, but indicated at 44 ) with the bottom channel of clamp manifold 45 .
  • Tubing 46 connects the bottom channel of clamp manifold 45 with the bottom left channel 18 a of clamp manifold 18 .
  • Channel 18 a is a mixing zone for buffer from bag 7 and unwashed cells from bag 44 .
  • Tubing 43 is connected to a starting cells spike coupler 47 .
  • Bag 48 is a bag for antibody which reacts specifically with cells to be selected on the Isolex® 300i. For example, where CD34+ cells are to be selected, bag 48 will contain anti-CD34 antibody.
  • the bag has an injection site 49 for injection of the antibody solution and an outlet port 50 connected to a sterilizing filter 51 .
  • Tubing 52 connects sterilizing filter 51 to the bottom channel of clamp manifold 45 .
  • Bag 53 is a bag for a peptide release agent which displaces the antibody from the cells after the cells have been magnetically selected. Bag 53 has an injection site 54 a for injection of a solution of the peptide and an outlet port 54 connected to a sterilizing filter 55 . Tubing 56 connects sterilizing filter 55 to the bottom channel of clamp manifold 45 .
  • Cylinder 57 is the primary magnet separation chamber. It has a vent filter 59 and an injection site 58 for injection of paramagnetic microbeads coated with an antibody which binds specifically to the antibody in bag 48 . It has a bottom port 60 which serves as both inlet and outlet for cell suspensions. In use it is mounted on a rocker mechanism as described in Moubayed et al. U.S. Pat. No. 5,536,475. Port 60 is connected by tubing 61 to the bottom left channel of clamp manifold 16 . That channel is connected by tubing 62 to the right top channel of clamp manifold 16 . The top right channel of manifold 16 is connected by tubing 72 to the top right chamber of clamp manifold 25 .
  • the bottom left channel of clamp manifold 16 is also connected by tubing 63 to Y-connector 64 and the latter is connected by tubing 65 to the bottom channel of clamp manifold 45 .
  • Y-connector 64 is also connected by tubing 66 to a pressure transducer protector 67 .
  • Bag 68 is the secondary magnet separation bag described in Moubayed et al. U.S. Pat. No. 5,536,475. It has inlet port 69 and outlet port 70 . Inlet port 69 is connected by tubing 71 to the bottom left channel of clamp manifold 18 . Outlet port 70 is connected by tubing 73 to the bottom right channel of clamp manifold 18 .
  • Bag 74 is a selected cell wash bag. It has two bottom ports. Inlet port 75 is connected by tubing 77 which has a sampling device 77 a to the bottom right channel 9 b of clamp manifold 9 . Outlet port 76 is connected by tubing 78 to the bottom left channel of clamp manifold 9 . If desired, an IsoFlowTM bag can be substituted for the selected cell wash bag.
  • Bag 79 is an end product bag. It has an injection site 80 and an inlet port 81 .
  • Tubing 82 carrying sampling device 82 a and clamp 83 connects inlet port 81 with the bottom channel of clamp manifold 45 .
  • Frame 84 is an organizer frame as described in Denieaga et al. International Publication WO 95/14142 for use with a peristaltic pump assembly (not shown) as described in Chapman et al. International Publication WO 95/13837.
  • Tubing 13 , 15 , 26 and 46 each passes through one of the four pumping modules of the peristaltic pump assembly.
  • the volume of bags can vary, depending upon the volume of cells to be processed.
  • each of bags 30 , 36 and 39 has a volume of 2000 ml
  • each of bags 48 , 53 and 79 has a volume of 150 ml
  • bag 74 has a volume of 600 ml.
  • the IsoFlowTM bag 5 has a volume of 400 ml.
  • the disposable set of FIG. 2 is placed on the Isolex 300i.
  • Bag 7 containing buffer and bag 44 containing source cells are attached.
  • the source cells are typically a leukapheresis product from a cell separation device such as a Fenwall 3000 CS.
  • the buffer bag has a capacity of 4000 ml and a starting volume of at least 3500 ml.
  • the cell source bag has a capacity of 1000 ml and a starting volume of about 500 ml.
  • buffer solution is added to the following elemments and connecting tubing to prime the system: IsoflowTM bag 5 , secondary magnet pouch 68 , spinning membrane filter 6 , filtrate bag 30 , selected cell wash bag 74 , release agent bag 53 , antibody bag 48 , cell source bag 44 .
  • IsoflowTM bag 5 secondary magnet pouch 68
  • spinning membrane filter 6 filtrate bag 30
  • selected cell wash bag 74 selected cell wash bag 74
  • release agent bag 53 selected cell wash bag 74
  • antibody bag 48 cell source bag 44
  • cell source bag 44 cell source bag
  • clamps in clamp manifold 45 are designated clamps C 1 , C 2 , C 3 , C 4 ; clamps in clamp manifold 9 are designated C 5 , C 6 ,C 7 , C 8 ; clamps in clamp manifold 16 are designated C 9 , C 10 , C 11 , C 12 ; clamps in clamp manifold 18 are designated C 13 , C 14 , C 15 , C 16 ; clamps in clamp manifold 25 are designated C 17 , C 18 , C 19 , C 20 ;
  • the pump on tubing 46 is designated P 1 , the cell source pump; the pump on tubing 15 is designated P 2 , the buffer pump; the pump on tubing 13 is designated P 3 , the recirculation pump; the pump on line 26 is designated P 4 , the filtrate pump; and the rotor of spinning membrane filter 6 is designated
  • clamps C 6 , C 8 , C 10 , C 11 , C 12 , C 14 , C 16 and C 20 are opened, pumps P 2 , P 3 , P 4 and P 5 are moving. This circulates buffer solution from bag 7 , into the inlet port 11 and out of outlet ports 14 and 24 of spinning membrane filter 6 , into bottom port 1 and out of top port 2 of IsoFlowTM bag 5 , and into filtrate bag 30 .
  • clamps C 1 , C 6 , C 8 , C 12 , C 14 , C 16 and C 20 are open, pumps P 1 , P 2 , P 3 , P 4 , and P 5 are moving.
  • a suspension of unwashed blood cells is withdrawn from cell source bag 44 through tubing 43 to the bottom channel of clamp manifold 45 , then out through tubing 46 to the bottom left channel 18 a of clamp manifold 18 where it is mixed with buffer solution.
  • the buffer solution is withdrawn from buffer bag 7 through tubing 15 to the top right channel of clamp manifold 16 , then out through tubing 17 to the bottom left channel 18 a of clamp manifold 18 .
  • the diluted suspension of blood cells in buffer solution flows out of the bottom left channel 18 a through tubing 19 into the bottom right channel of clamp manifold 18 , then out through tubing 20 to the bottom right channel 9 b of clamp manifold 9 , where it is mixed with additional buffer solution from top port 2 of IsoflowTM bag 5 .
  • the diluted suspension of blood cells in buffer solution flows from channel 9 b through tubing 10 to the inlet port 11 of spinning membrane filter 6 . Platelets, a few red cells, and buffer flow through the membrane and out through outlet port 24 through tubing 23 to the top right channel of clamp manifold 25 , then out through tubing 26 and 28 to filtrate bag 30 (clamp 31 open, clamp 40 closed).
  • a concentrated suspension of blood cells in buffer flows from the exit port 14 of spinning in membrane filter 6 through tubing 13 to the bottom left channel of clamp manifold 9 , then out through tubing 12 through the bottom port 1 into IsoflowTM bag 5 .
  • a suspension of blood cells in buffer solution flows out of the top of the IsoflowTM bag 5 .
  • These cells are mixed in mixing zone 9 b with unwashed cells from source bag 44 and are recirculated through the spinning membrane filter 6 . Recirculation washing is continued until the desired level of platelet removal has been achieved.
  • antibody in buffer solution is transferred to the concentrated suspension of blood cells in buffer solution in the IsoflowTM bag 5 .
  • clamps C 3 , C 6 , C 8 , C 14 , C 16 and C 20 are open and pumps P 1 , P 3 and P 5 are moving.
  • the antibody and cells are mixed in mixing zone 9 b .
  • the antibody tubing is rinsed with buffer solution while the antibody/cell suspension circulates through the IsoflowTM bag 5 and spinning membrane filter 6 . This occurs with clamps C 6 , C 8 , C 10 , C 11 , C 14 , C 16 and C 20 open,and with pumps P 1 , P 2 , P 3 and P 5 moving.
  • the antibody/cell suspension is circulated through the IsoflowTM bag 5 and spinning membrane filter 6 to sensitize the cells by binding with the antibody. This is accomplished with clamps C 6 , C 8 and C 20 open, and with pumps P 3 and P 5 moving.
  • Buffer solution is withdrawn from buffer bag 7 through tubing 15 , clamp manifold 16 , tubing 17 , clamp manifold 18 (left channel), tubing 19 , clamp manifold 18 (right channel) and tubing 20 , as previously described, to mixing zone 9 b , where it is mixed with the suspension of blood cells from IsoflowTM bag 5 to form a diluted suspension of blood cells containing excess unbound antibody.
  • This diluted suspension flows through tubing 10 to inlet port 11 of the spinning membrane filter 6 .
  • Filtrate comprising antibody in buffer solution flows out of outlet port 24 , through tubing 23 , clamp manifold 25 , tubing 26 , tubing 28 , and port 29 into filtrate bag 30 .
  • a concentrated suspension of blood cells in buffer solution flows from the outlet port 14 of the spinning membrane filter 6 , through tubing 13 , clamp manifold 9 (bottom left channel), tubing 12 and bottom port 1 into IsoflowTM bag 5 .
  • the recirculation washing is continued until the cell suspension contains the desired level of unbound antibody.
  • the cells are transferred to primary magnet separation chamber 57 .
  • Antibody-coated paramagnetic microbeads are mixed with the cells to form a conjugate between the microbeads and the sensitized cells, the conjugate is magnetically separated from the non-sensitized cells, the non-sensitized cells are transferred to waste bag 36 , peptide release agent from bag 53 is added to the chamber 57 to release the selected cells, the selected cells are transferred to the secondary magnet separation bag where any remaining microbeads are separated magnetically, and the selected cells are transferred to selected cell wash bag 74 .
  • the selected cells are then recirculation washed to remove excess peptide release agent using spinning membrane filter 6 , all in conventional manner.
  • selected cell wash bag can be an IsoflowTM bag, and the recirculation wash to remove peptide release agent can be conducted using the method of this invention. After removal of peptide release agent, the selected cells are transferred to end product bag 79 .
  • FIG. 3 illustrates a disposable set of the invention which is adapted for use on a stand-alone cell washing apparatus, i.e., an apparatus which does not include a cell selection function such as the magnetic cell selection of the Isolex® 300i instrument.
  • the disposable set includes IsoflowTM bag 5 having top port 2 and bottom port 1 , spinning membrane filter 6 having inlet port 11 for a diluted suspension of blood cells, outlet port 14 for a concentrated suspension of blood cells, and outlet port 24 for filtrate, and filtrate bag 30 having inlet port 29 . It may also include one or more of washed cell bag 79 having outlet port 81 , unwashed cell bag 44 having outlet port 47 , and buffer solution bag 7 having outlet port 21 .
  • Top port 2 of IsoflowTM bag 5 is connected by tubing 8 to connector 89 .
  • Port 21 of buffer bag 7 is connected by tubing 15 to Y-connector 95 and the latter is connected by tubing 20 carrying clamp C 1 to connector 89 .
  • Port 47 of unwashed cell bag is connected by tubing 43 carrying clamp C 3 to Y-connector 93 and then by tubing 91 to connector 89 .
  • Connector 89 serves as a mixing zone for unwashed cells in buffer solution from bag 44 , recirculating cells in buffer solution from bag 5 and buffer solution from bag 7 .
  • Connector 89 is connected by tubing 10 to inlet port 11 of spinning membrane filter 6 .
  • Filtrate outlet port 24 of spinner 6 is connected by tubing 23 to Y-connector 94 and by tubing 26 to the inlet port 29 of filtrate bag 30 .
  • Connector 95 is connected by tubing 92 carrying clamp C 2 to connector 94 .
  • Connector 94 is connected by tubing 41 to pressure transducer 90 .
  • Oulet port 14 of spinner 6 is connected by tubing 13 to the bottom port 1 of IsoflowTM bag 5 .
  • Y-connector 93 is connected by tubing 82 carrying clamp C 4 to inlet port 81 of washe
  • a suspension of blood cells in buffer solution is withdrawn from the IsoflowTM bag 5 through the top port 2 and flows through tubing 8 to mixing zone 89 .
  • Unwashed cells in buffer solution are withdrawn from bag 44 through port 47 and (with clamp C 3 open and clamp C 4 closed) through tubing 43 to Y-connector 93 and then through tubing 91 to mixing zone 89 by the transfer pump P 2 .
  • Buffer solution is withdrawn from bag 7 through port 21 and tubing 15 to connector 95 by the buffer pump P 2 . With clamp C 1 open, buffer flows through tubing 20 to mixing zone 89 .
  • a diluted suspension of blood cells in buffer solution flows from mixing zone 89 through tubing 10 to inlet port 11 of spinner 6 .
  • a concentrated suspension of blood cells in buffer solution flows through outlet port 14 of spinner 6 through tubing 13 and inlet port 1 into IsoflowTM bag 5 by recirculation pump P 3 .
  • Filtrate flows through outlet port 24 in spinner 6 and tubing 23 to connector 94 and, with clamp C 2 closed, through tubing 26 and inlet port 29 into filtrate bag 30 by pump P 4 .
  • Recirculation washing is continued until the desired amount of target component has been removed from the blood cells.
  • Clamps C 1 , C 2 and C 3 are then closed, clamp C 4 is opened, and the direction of pump P 1 is reversed, so that the suspension of washed cells flows from bag 5 through tubing 8 , 91 and 82 and port 81 into washed cell bag 79 .
  • the lines, bag and spinner are then rinsed by closing clamps C 1 and C 3 , opening clamps C 4 and C 2 , and pumping buffer with pump P 2 in series with pumps P 1 and P 3 to rinse the spinner, IsoflowTM bag and tubing.
  • the filtrate rate (f) is typically fixed at about 70 ml/min.
  • the recirculation rate (r) provides the primary pressure regulation (using the concentration ratio CR described below) and varies from 14 to 70 ml/min.
  • the buffer solution rate (b) ranges from 0 to 70 ml/min. to maintain a minimum scale volume and as a secondary pressure regulation mechanism.
  • the rotor of the spinning membrane filter operates at a maximum of 3700 RPM and a minimum of about 2340 RPM during normal processing.
  • the Isolex® 300i system is automatically controlled using microprocessors. These microprocessors in-turn control 5 banks of 4 clamps each (clamps C 1 -C 20 ), 1 bank of pumps (pumps P 1 -P 4 ), 1 spinner motor drive P 5 (drive for the rotor of spinning membrane filter 6 ), and 1 rocker assembly for container 57 with an integral magnet carriage to facilitate separation of magnetic beads (not shown, but described in Moubayed et al. U.S. Pat. No. 5,536,475).
  • the system uses feedback from 6 weight scales (not shown), 2 pressure transducers (not shown, but attached to line 66 at 67 and to line 41 at 42 , and 3 sets of fluid and tubing detectors (not shown but attached to lines 61 , 66 and 41 ).
  • the bags 44 , 53 , 48 and 79 are hung on weight scales 1 , 2 , 3 and 4 , respectively.
  • Bags 74 and 5 are hung together on weight scale 5 .
  • Buffer bag 7 is hung on weight scale 5 .
  • Buffer bag 7 is hung on weight scale 6 .
  • Bags 36 , 39 and 30 are not hung on a scale.
  • Weight scale 5 is used to determine the cell product volume in the wash circuit by substracting out the reference weight when the IsoflowTM bag is empty.
  • the weight scales are in the tower of the Isolex® 300i instrument.
  • the stand-alone cell washing system will also run automatically using microprocessors. These microprocessors in turn control 1 bank of 4 clamps each, 1 bank of 4 pumps and 1 spinner motor drive. The system will require feedback from 4 weight scales, 2 pressure transducers, and 3 sets of fluid and tubing detectors.
  • CR concentration ratio
  • the cells are concentrated and washed automatically. We have found that by concentrating, diluting, and concentrating again multiple times, the volume can be more consistently controlled. Thus, between every other cell product cycle through the spinner (i.e., spinning membrane filter) the cell volume is diluted and reconcentrated. If the number of cycles left is predicted to be less than 2.5 cycles, the dilutions stop. During dilutions, the filtrate pump P 4 is stopped, the buffer pump P 2 runs at a fixed rate and the recirculation pump P 3 runs at about 110% of the buffer rate. This allows the membrane to be rinsed and dilutes the cell concentrate through the port with the more concentrated cells.
  • the spinner i.e., spinning membrane filter
  • the transmembrane pressure is regulated by controlling the concentration ratio CR using the recirculation pump P 3 .
  • the concentration ratio CR is controlled to a target pressure by a PID (Proportional/Integrative/Derivative) control through the pressure measurements.
  • Filtrate rate (f) is set to its maximum in order to minimize the time to process the cells.
  • Filtration pressure is an indicator of the concentration of blood cells along the membrane of the spinning membrane filter.
  • the ratio of the measured spinner 6 , buffer pump, or recirculation pump rate to the respective commanded rate is calculated.
  • the filtrate rate is further reduced when the pressure error (E p ) described above is less than ⁇ 5 mmHg.
  • E p pressure error
  • the filtrate rate is set to 0.
  • Recirculation rate (r) is the primary regulating variable.
  • the buffer solution rate (b) is used to regulate the concentration ratio CR between values of 1 and 2.
  • the buffer pump P 2 provides the primary regulation to the scale weight management control.
  • the buffer is commanded to about 78 mmin. This is approximately 8 ml/min faster than the filtrate pump P 4 . This causes the bag weight to rise.
  • the buffer once again becomes secondary to the concentration ratio control, the buffer pump P 2 is regulated according to the equation
  • the controller automatically adjusts the rotor spin rate of the spinning membrane filter.
  • t and v are time and volume, respectively, in the spinning membrane.
  • the amount of washing is based on an estimate of “residual”.
  • the residual represents the target component for reduction (e.g., platelets, antibody). This estimate is made possible by the mixing properties of the IsoFlowTM bag. The estimate is calculated similar to how serial dilutions would calculate the residual. However, it is recalculated several times a second. The equation is
  • FSR i FSR i ⁇ 1 ⁇ (F i /(B i +C i ) ⁇ (C i /V i ) ⁇ FSRW 1 ⁇ 1 ⁇ TA)
  • FSR i Fraction of Starting Residual at time t i
  • FSR i ⁇ 1 Fraction of Starting Residual at time t i ⁇ 1
  • B i Buffer volume moved at rate b measured at time interval i ⁇ 1 to i in units of ml
  • C i Cell source moved at rate c measured at time interval i in units of ml, including the rate from the IsoFlowTM bag 5 , as well as the rate of addition of unwashed cells, if any, in same units
  • V i cell product volume at time interval i in ml
  • the Target Admittance is the unitless constant that represents the ease with which a given substance passes through the membrane (the inverse of membrane impedance).
  • the Target Admittance has been found to be between 0.5 and 1.0 with a preferred setting of 0.7.
  • Target Admittance has been found to be between 0.7 and 1.2 with a preferred setting at 1.
  • the optimal level for the antibody used for CD34+ selection on the Isolex® 300i has been found to be in the range of 50-150 micrograms.
  • R j Recirculation volume moved at rate r measured at time interval j in units of ml
  • Cell cycles i Number of cycles through the spinning membrane device that the cell product has experienced at time interval i.

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US09/004,344 US6251295B1 (en) 1998-01-08 1998-01-08 Method for recirculation washing of blood cells
CA002644322A CA2644322A1 (fr) 1998-01-08 1999-01-07 Procede, sac et ensemble jetable pour le lavage de cellules sanguines par recirculation
AU21110/99A AU744878B2 (en) 1998-01-08 1999-01-07 Method, bag and disposable set for recirculation washing of blood cells
PCT/US1999/000535 WO1999034848A1 (fr) 1998-01-08 1999-01-07 Procede, sac et ensemble jetable pour le lavage de cellules sanguines par recirculation
JP2000527295A JP4307714B2 (ja) 1998-01-08 1999-01-07 血球を再循環洗浄するのに用いる方法、バッグおよび使い捨てセット
EP99901408A EP1058564B1 (fr) 1998-01-08 1999-01-07 Ensemble jetable pour le lavage de cellules sanguines par recirculation
AT99901408T ATE314869T1 (de) 1998-01-08 1999-01-07 Wegwerfset zum umlaufwaschen von blutzellen
CA002569912A CA2569912C (fr) 1998-01-08 1999-01-07 Procede, sac et ensemble jetable pour le lavage de cellules sanguines par recirculation
CA002317756A CA2317756C (fr) 1998-01-08 1999-01-07 Procede, sac et ensemble jetable pour le lavage de cellules sanguines par recirculation
ES99901408T ES2257028T3 (es) 1998-01-08 1999-01-07 Juego desechable para el lavado por recirculacion de celulas sanguineas.
DE69929303T DE69929303T2 (de) 1998-01-08 1999-01-07 Wegwerfset zum umlaufwaschen von blutzellen
US09/863,485 US20010035377A1 (en) 1998-01-08 2001-05-23 Recirculation container
JP2007297162A JP4829205B2 (ja) 1998-01-08 2007-11-15 血球を再循環洗浄するのに用いる方法、バッグおよび使い捨てセット

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AU (1) AU744878B2 (fr)
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DE (1) DE69929303T2 (fr)
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US20010035377A1 (en) 2001-11-01
JP2002500071A (ja) 2002-01-08
WO1999034848A1 (fr) 1999-07-15
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